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Original article
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Peer reviewed article
Clinical experience with mycophenolate
mofetil in systemic autoimmune conditions
refractory to common immunosuppressive
therapies
Cédric Bandeliera, Pierre-André Guerneb, Stéphane Genevayb, Axel Finckhb, Cem Gabayb
a
b
Clinique de Carouge, Réseau La Tour, Geneva, Switzerland
Division of Rheumatology, University Hospitals of Geneva, Switzerland
Summary
Objectives: Standard therapies against inflammatory rheumatic diseases consist of immunosuppressive drugs with high toxicities and many sideeffects. Except in the treatment of systemic lupus
erythematosus with renal involvement, controlled
studies with mycophenolate mofetil (MMF) are
lacking in other autoimmune and inflammatory
systemic diseases. Here we describe our clinical
experience with MMF in several unusual indications.
Methods: We collected data including serological findings, adverse events and response to
treatment in eleven patients with autoimmune
diseases including systemic lupus erythematosus
(SLE), mixed connective tissue disease (MCTD),
polymyositis (PM), diffuse systemic sclerosis that
were treated in our rheumatology unit.
Results: Our results show remission in ten patients with minimal side effects and reduced prednisone dosage. The median dose of MMF was 2 g
per day. Adverse events were limited, with one
case of leucopenia, one tachycardia and one colitis. One patient definitively stopped the treatment
because of side effects.
Conclusions: MMF seems to be a very powerful and attractive alternative medication in the
treatment of immune-mediated inflammatory
diseases. The good tolerance and safety profile
makes it an excellent therapeutic option permitting a global reduction of corticosteroids doses.
Key words: mycophenolate mofetil; immunosuppressant; autoimmune rheumatic diseases
Introduction
No conflict of
interest to declare.
Mycophenolate mofetil (MMF, Cellcept®) is
an immunosuppressive drug used in organ transplantation with the aim of reducing acute rejection episodes. Mycophenolate mofetil has immunomodulating effects by inhibiting de novo
purine synthesis, which leads to decreased proliferation of activated lymphocytes, thus resulting in
reduction of antibody production, changes in the
recruitment and induction of apoptosis [1].
More recently, MMF has also been used as a
novel therapy for systemic lupus erythematosus
(SLE) with renal involvement [2, 3], essentially in
refractory cases and patients intolerant to conventional immunosuppressive regimens [4–6]. In ad-
dition, some studies reported encouraging results
regarding MMF as an alternative therapy for
treating SLE with and without renal involvement
as well as other immune-mediated rheumatologic
diseases such as polymyositis, systemic vasculitis
and autoimmune haemolytic anaemia [7–12].
However, the literature supporting the efficacy of
MMF in the treatment of inflammatory rheumatic diseases is scarce, with only few prospective
studies and case reports. Therefore, we decided to
collect and describe our clinical experience on all
patients with different immune-mediated rheumatic diseases treated with MMF, and to compare
our results with a review of the literature.
Clinical experience with mycophenolate mofetil in systemic autoimmune conditions refractory to common immunosuppressive therapies
42
Patients and methods
We retrospectively studied eleven consecutive patients with inflammatory rheumatic diseases who were
followed in our unit from the start of MMF treatment
until December 2007, and who received at least one dose
of MMF. All data were collected from clinical chart reviews and interviews with the different specialists involved in the follow up of the patients.
The diagnosis of SLE was based on the American
College of Rheumatology (ACR) 1982 revised criteria for
the classification of SLE [13]. The diagnosis of
polymyositis was based upon the criteria of Bohan and
Peter [14, 15]. The diagnosis of mixed connective tissue
disease (MCTD) was established according to AlarconSegovia’s criteria using serologic (anti-RNP antibodies)
and clinical findings [16]. We have used the ACR criteria
for the diagnosis of systemic sclerosis [17].
All the data included details regarding initial presentation and global evolution of disease activity up to December 2007. We documented all the treatments prior to
the introduction of MMF as well as concomitant treatments in combination with MMF. We examined all
significant changes following the initiation of MMF.
Patient’s records were also studied for details on the
occurrence of adverse events. We also collected laboratory results on autoantibody tests. Similarly to previous
studies, we operationally defined a successful therapeutic
response as a complete resolution of clinical symptoms, a
normalisation of biological markers of inflammation and
a reduction of concomitant anti-rheumatic therapies particularly corticosteroids.
Autoantibody determinations were performed in the
Clinical Immunology and Allergy Laboratory of the
Geneva University Hospitals. Anti-nuclear antibody
(ANA) detection was performed by indirect immunofluorescence (IFI) technique using Hep-2 substrate slides and
FITC anti-human IgG conjugates (Nova Lite™ Inova
Diagnostics, San Diego, USA). Anti-neutrophil cytoplasmic antibody (ANCA) detection was performed by IFI
technique using ethanol-fixed human neutrophil and formalin-fixed human neutrophil substrate slides and FTIC
anti-human IgG conjugate (Nova Lite™ Inova Diagnostics). Anti-double-stranded DNA antibody detection was
performed by IFI technique using Crithidia luciliae slides
and FTIC anti-human IgG conjugate (Nova Lite™
Inova Diagnostics). Anti-nucleoproteins detection and
quantification were performed using specific ELISA kits
(Quanta Lite™ ENA 6, Inova Diagnostics; Quanta
Lite™ SS-A / SS-B / RNP / Sm / Jo-1 / Scl-70). AntiMPO and PR3 detection and quantification were performed using specific ELISA kits (Quanta Lite™ MPO /
PR3, Inova Diagnostics).
Results
Patient description
Nine of the eleven patients were female and
the median age was 41 years (range 16–68) at the
time of MMF initiation. The following diseases
were treated with MMF and reviewed in this article: SLE (six patients), polymyositis (two patients),
MCTD (two patients), systemic sclerosis (one patient). The median disease duration before the
start of MMF was 38 months (rang 17–114), the
median age at time of diagnosis was 36 years
(range 13–63). In table 1 we describe the list of
previous treatments and disease characteristics.
All diagnoses were already established at the
start of MMF therapy. One patient with SLE had
concomitant psoriatic arthritis, a further SLE patient also suffered from multiple sclerosis and a
third SLE case exhibited features of Evans syndrome, including the combination of autoimmune
haemolytic anaemia and thrombocytopenia. All
these concomitant manifestations were present
before the start of MMF therapy.
Previous treatments
Patients received a median of three anti-inflammatory or immunosuppressive drugs (range
from two to five drugs) to treat their respective
diseases, including prednisone, colchicine,
methotrexate, azathioprine, cyclosporin A, cyclophosphamide, hydroxychloroquine, intravenous
immunoglobulins, interferon beta, etanercept,
infliximab, and rituximab (see details in table 1).
Among the six SLE patients, MMF was initiated
because of incomplete or poor response to previous treatments in four cases, whereas the two others promptly received MMF because of the presence of renal involvement. Two patients with
polymyositis had refractory active disease despite
a combination of prednisone and methotrexate.
Two MCTD patients had inadequate disease control despite immunosuppressive treatment and, in
addition, one of them had to stop azathioprine as a
consequence of digestive intolerance. Azathioprine was discontinued in the patient with systemic sclerosis because of cutaneous allergy.
MMF treatment
The dosages of MMF, treatment duration and
clinical evolution are shown in table 2. The median daily dose of MMF was 2 g (range 1–3 g) and
median treatment duration was 29 months (range
4–67). Patients took a median of two concomitant
medications (range 1–3).
Follow-up
Among the six patients with SLE, three had
renal involvement. Other manifestations included
psoriatic arthritis, multiple sclerosis, Evans syndrome and more classical lupus symptoms such as
alopecia, fever or aphtosis. The SLE disease activity index (SLEDAI) [18] was determined according to clinical and biological manifestations before the start of MMF and ranged from 12 to 21
(median = 17). The median prednisone dosage was
37.5 mg (range 10–60). The median MMF treat-
S W I S S M E D W K LY 2 0 0 9 ; 1 3 9 ( 3 – 4 ) : 4 1 – 4 6 · w w w . s m w . c h
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Table 1
Baseline data.
Case Diagnosis
no
Date of
diagnosis
Age at time
of diagnosis
(years)
Sex
Initial
Autoantibodies
manifestations
Previous
treatments*
Prednisone
dosage before
MMF start
(mg/d)
Other clinical/
biological
parameters
measured before
MMF start
Indication for
MMF treatment
1
SLE
2001
37
F
Arthralgia,
aphtosis,
cutaneous
vasculitis, GN
ANA +
Anti-dsDNA +
MTX
PDN
15
SLEDAI = 20
Polyarthralgia,
aphtosis,
vasculitis, GN
2
Polymyositis 2003
56
F
Asthenia,
weakness,
arthralgia,
erythema
ANA +
Anti-SSA +
Anti-Jo1 +
MTX
PDN
RTX
10
CK 1587 (U/L)
Active myositis
3
MCTD
2005
33
F
Synovitis,
myalgia,
livedo
ANA +
Anti-U1RNP +
PDN
HCQ
MTX-AZA
INF
20
CK 1184 (U/L)
Asthenia,
myalgia,
arthralgia
4
Diffuse
systemic
sclerosis
2003
63
F
Raynaud,
cutaneous
ulcers, diffuse
scleroderma
ANA +
AZA
PDN
20
Diffuse skin
involvement, no
other organ
involvement
AZA allergy
5
SLE +
psoriatic
arthritis
2004
30
M
Arthritis
ANA +
Anti-dsDNA +
PDN
MTX
ETN
10
SLEDAI = 21
Arthralgia, GN
6
SLE +
multiple
sclerosis
2005
41
F
Asthenia,
arthralgia
ANA +
Anti-dsDNA +
Anti-U1-RNP +
PDN
IFN-β
30
SLEDAI = 16
Active
polyarthritis,
serositis and
digital necrosis
7
SLE +
Evans
syndrome
1999
13
F
Polyarthritis,
ANA +
asthenia,
Anti-dsDNA +
headache,
Anti-U1-RNP +
anemia,
thrombocytopenia
PDN
AZA-HCQ
50
SLEDAI = 17
Evans syndrome,
polyarthralgia
8
MCTD
2002
28
F
Myositis,
asthenia,
scleroderma
ANA +
Anti-U1-RNP +
CYC
PDN
20
CK 1220 (U/L)
Myositis,
dyspnea,
asthenia
9
Polymyositis 1993
54
M
Weakness,
myositis
ANA +
PDN
AZA-MTXCSA
IVIg
15
CK 600 (U/L)
Active myositis
10
SLE
2002
26
F
Asthenia,
arthralgia,
rash, GN
ANA +
Anti-dsDNA +
PDN
HCQ
NSAID
60
SLEDAI = 16
Arthralgia, GN
11
SLE
2005
13
F
Arthralgia,
alopecia,
aphtosis
ANA +
Anti-dsDNA +
PDN
HCQ
MTX
60
SLEDAI = 12
Arthralgia,
alopecia,
fever
ANA: antinuclear antibodies; anti-ds DNA: anti-double stranded DNA; AZA: azathioprine; CK normal range: 47–222 U/L; CSA: cyclosporin A;
CYC: cyclophosphamide; ETN: etanercept; GN: glomerulonephritis; HCQ: hydroxychloroquine; IFN-β: interferon beta; INF: infliximab; IVIg: intravenous
immunoglobulins; MCTD: mixed connective tissue disease; MMF: mycophenolate mofetil; MTX: methotrexate; NSAID: non steroidal anti inflammatory drug;
PDN: prednisone; RTX: rituximab; SLE: systemic lupus erythematosus; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index
* treatments were frequently combined
ment duration was 30 months (range 4–67) up to
December 2007. At the last follow-up visit all
patients exhibited clinical and biological signs of
improvement. The median SLEDAI score was 4
(range 0–7). In addition the dosage of prednisone
could be reduced in five of six patients to values
under 10 mg/day (mean 6 mg, range 0–20).
The two patients with polymyositis exhibited
clinical and biological signs of active disease prior
to starting therapy with MMF. CK values were
1587 (U/L) and 600 (U/L), respectively. At the
end of the follow-up period both patients
achieved total remission, the CK values dropped
to 82 and 142 (U/L) and prednisone dosages to
15 and 2.5 mg per day, respectively.
In the two cases of MCTD, one patient had
severe and refractory disease that did not respond
to previous treatment with methotrexate, azathioprine, hydroxychloroquine, or concomitant immunotherapy with infliximab. Remission was only
achieved when the MMF dosage reached 2 g/d. In
addition, CK levels decreased from 1184 (U/L) to
238 (U/L) after one year. The other patient with
MCTD had symptoms of dyspnoea, asthenia and
myalgia with elevated CK levels reaching 1220
(U/L) at the start of the MMF treatment. After
Clinical experience with mycophenolate mofetil in systemic autoimmune conditions refractory to common immunosuppressive therapies
Table 2
Follow-up data.
Case
no
44
MMF
treatment
initiation
MMF
dosage
(g/d)
Other
concomitant
treatments
MMF
total
treatment
duration
(month)
MMF
side effects
Prednisone
dosage at the end
of the follow-up
(mg/d)
Other clinical/
biological parameters
measured at the end
of the follow-up
1
06/2004
3
PDN
MTX
RTX
43
None
2.5
SLEDAI = 6
2
06/2005
2
PDN
MTX
22 + 5
(stopped in
April 07 and
started again
in August 07)
Diarrhea, colitis
15
CK 82 (U/L)
3
07/2006
2
PDN
MTX
RTX - INF
18
Transient
leucopenia
0
CK 238 (U/L)
4
06/2005
2
PDN
4
(stopped in
October 05)
Tachycardia
5
/
5
11/2006
1.5
PDN
ETN
14
None
5
SLEDAI = 7
6
07/2006
3
PDN
IFN-β
18
None
20
SLEDAI = 4
7
07/2006
1
PDN
RTX
18
None
3
SLEDAI = 2
8
03/2004
2
PDN
46
None
10
CK 174 (U/L)
9
06/2002
2
PDN
IVIg
67
None
2.5
CK 142 (U/L)
10
10/2002
2
PDN
HCQ
63
None
0
SLEDAI = 2
11
10/2007
1
PDN
HCQ
7
None
5
SLEDAI = 4
CK normal range: 47–222 (U/L); ETN: etanercept; HCQ: hydroxychloroquine; IFN-β: interferon beta; INF: infliximab;
IVIg: intravenous immunoglobulins; MMF: mycophenolate mofetil; MTX: methotrexate; PDN: prednisone; RTX: rituximab;
SLEDAI: Systemic Lupus Erythematosus Disease Activity Index
one year of therapy, we observed an improvement
in clinical and biological parameters (CK levels at
174 U/L) allowing the prednisone dosage to be
reduced from 20 to 10 mg daily. MMF treatment
was prescribed to one patient with diffuse systemic sclerosis who had no organ involvement.
However, MMF had to be stopped four months
later due to symptomatic tachyarrhythmia confirmed by 24h-Holter measurement and attributed to the medication. Cardiological investigations including echocardiography, thyroid
hormone dosage and specialist consultation were
normal and reassuring. The arrhythmia resolved
after treatment discontinuation. Her condition
remained stable on low dose prednisone.
Side effects
One patient with polymyositis developed active colitis with major weight loss 22 months after
starting MMF leading to treatment discontinuation and resolution of digestive symptoms. However, the polymyositis relapsed after four months
and MMF therapy was resumed with good clinical response and no intestinal problems after a
follow-up of ten months. One patient had transient leucopenia that resolved without treatment
discontinuation.
Discussion
Mycophenolate mofetil is an immunosuppressant used since the early nineties to reduce the
occurrence of allograft rejection in renal transplantation. More recently it has also been prescribed to induce and maintain remission of severe lupus nephritis and thereafter to treat various
other immune-mediated inflammatory diseases.
In our case review, we observed that MMF alone
or in combination with other immunosuppressive
therapies was effective in controlling disease
activity in patients with SLE, MCTD, and
polymyositis. Furthermore, MMF was generally
well tolerated and adverse events were relatively
mild and reversible. These encouraging findings
further suggest that MMF may be very useful in
the treatment of connective tissue diseases refrac-
S W I S S M E D W K LY 2 0 0 9 ; 1 3 9 ( 3 – 4 ) : 4 1 – 4 6 · w w w . s m w . c h
tory to other treatments or requiring more toxic
medications such as cyclophosphamide. All the
patients were followed in the same centre and
considerations whether the treatment was useful
were based upon global evaluation from the
physicians confirmed by biological parameters. In
all the patients who responded favourably to
MMF therapy we also noticed that the dosage of
corticosteroids was progressively tapered, suggesting a possible steroid sparing effect of MMF.
The beneficial effect of MMF in the treatment of lupus nephritis has been reported in randomised controlled clinical trials in comparison
with cyclophosphamide [2, 19]. In their review
concerning 86 patients with SLE, Pisoni et al
found a substantial benefit of using MMF on the
reduction of steroid dosage as well as on clinical
and biological markers of disease activity, including ECLAM, erythrocyte sedimentation rate, and
anti-double stranded DNA antibody titre in SLE
patients with renal involvement or refractory disease activity [4]. In addition, some studies in SLE
patients suggested that MMF is effective in controlling non-renal manifestations. Gaubitz et al
showed significant improvement in ten patients
with moderate and severe SLE after three months
of MMF [6]. Furthermore, the clinical benefit on
skin erythema, musculoskeletal symptoms, and
cytopenia persisted up to 16 months leading to a
reduction in steroid dosage. Karim et al reported
encouraging results in 21 refractory SLE patients
with clear benefit on disease activity allowing a
significant reduction of oral corticosteroid doses
with minimal side-effects [5]. In contrast, Pisoni
et al reported poor results in their review of seven
patients with skin manifestations refractory to
multiple treatments [20].
Considering the use of MMF in other immune-mediated rheumatologic diseases, promising results were observed in the control of
idiopathic inflammatory myopathy in a small
prospective study [8]. Six of seven patients had a
marked improvement of muscle weakness and all
of them demonstrated an impressive response regarding serum levels of muscle enzymes as well as
a reduction in prednisone dosage. Similarly, there
are other reports of significant improvement in
patients with severe refractory polymyositis
treated with MMF [21]. These results are consistent with our observation. Furthermore, MMF
discontinuation in one of our polymyositis patient
resulted in a disease flare despite treatment with
methotrexate (15 mg weekly) suggesting that
MMF played a critical role in maintaining the remission. In a small prospective open-label trial,
Liossis et al obtained encouraging results treating
five patients with systemic sclerosis and interstitial lung disease with MMF and low-dose prednisolone [22]. Nihtyanova et al reported that systemic sclerosis was adequately controlled in
109 patients during five years with a significantly
lower frequency of clinically significant pulmonary fibrosis and better five year survival [9].
45
Good results were observed in 28 rheumatoid
arthritis (RA) patients with reduced numbers of
painful and swollen joints and positive investigator and patient evaluation [23]. A multicentre,
36-week, randomised, dose escalating, placebo
controlled clinical trial including 217 patients
with severe refractory RA showed a modest clinical improvement with the highest dose (MMF 1 g
twice daily) [24]. In a subsequent 9-month, randomised double-blind trial including 356 RA patients comparing two doses of MMF, the results
showed that MMF 1 g twice daily was as effective
and better tolerated than MMF 2 g twice daily
[25]. To further examine the effect of MMF on
disease control, the patients included in this 9month study were re-randomised either to continue MMF (1 g or 2 g twice daily) or to receive a
placebo. The proportion of patients experiencing
a RA flare was lower in those treated with MMF
than in placebo groups [26]. A three-year open
label clinical trial in RA showed that MMF was
well tolerated and that the main side effects were
non serious gastrointestinal events [27]. All together, the results of clinical trials suggest that
MMF exerts a modest beneficial effect on RA disease activity. Unfortunately, none of these studies
has provided any data on the prevention of structural damage by MMF.
In our group of patients, there was one case of
diarrhoea with major weight loss. MMF discontinuation resulted in the complete resolution of
symptoms. In addition, this treatment was resumed after a few months without any further adverse event. We observed one case of transient
leucopenia, but no case of superimposed serious
infection.
There are some limitations to this study. Retrospective case studies, such as this one, are prone
to selection bias and missing data. We addressed
this by making every effort to include all patients
in our unit who had received MMF. All rheumatologists within the unit where personally encouraged to review their patients for cases treated with
MMF and data were reviewed for completeness
with their help. In addition, it is difficult to
analyse the effect of MMF alone as this treatment
was used in combination with corticosteroids and
other immunosuppressive drugs in several patients. Thus, it is important to consider the possible positive effect of drug combinations in the
treatment of autoimmune systemic diseases.
In conclusion, MMF is an interesting alternative for the treatment of several immune mediated inflammatory diseases. It appears to be especially effective in autoimmune connective tissue
diseases including SLE, polymyositis and MCTD.
Drug tolerance and safety profile seem good
compared to other immunosuppressive agents.
However, further prospective studies are needed
to compare benefits of MMF with other classical
immunosuppressive drugs.
Clinical experience with mycophenolate mofetil in systemic autoimmune conditions refractory to common immunosuppressive therapies
46
Acknowledgements
We would like to thank Mrs V. Garlow, F. HoffmannLa Roche, Palo Alto, USA for providing useful information on clinical trials with MMF in patients with rheumatoid arthritis.
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Correspondence:
Cem Gabay, MD
Division of Rheumatology
University Hospitals of Geneva,
26 Avenue Beau-Séjour
CH-1211 Geneva 14
Switzerland
E-Mail: [email protected]